[CCoE Notice] Thesis Announcement: Hamidreza Azargoshasb, "The Common Mechanism of Suppression of -hematin Crystallization by Artemisinin-class Antimalarials"

[Greenwell, Stephen J]

[Dissertation Defense Announcement at the Cullen College of Engineering]
The Common Mechanism of Suppression of •-hematin Crystallization by Artemisinin-class Antimalarials

Hamidreza Azargoshasb

November 20, 2024; 10 a.m. – 12 p.m.
Location: Chemical Engineering Conference Room (S234), Eng. Bldg. 1
Committee Chairs:
Peter G. Vekilov, Ph.D. | Jeffrey D. Rimer, Ph.D.
Committee Members:
Triantafillos J. Mountziaris, Ph.D. | Vincent Donnelly, Ph.D. | Ognjen Miljanic, Ph.D.
Abstract
Malaria, primarily caused by Plasmodium falciparum, remains a significant public health challenge in equatorial regions. In recent years, the malaria death toll has risen again due to the parasite's development of resistance to artemisinin and chloroquine. Consequently, the development of new antimalarial drugs is critical. During the erythrocyte phase, the parasite invades red blood cells, catabolizes hemoglobin, and sequesters toxic heme as hemozoin crystals. Several antimalarial drugs target this crystallization process.
Artemisinin (ART)-based drugs are activated in vivo through the release of heme, which generates carbon-centered radicals that damage the parasite. Studies have shown that heme–artemisinin adducts, formed following the radical activation of ARTs, effectively kill P. falciparum by inhibiting hematin crystallization. Most ART-based drugs are metabolized to dihydroartemisinin (DHA) in the body. Therefore, we hypothesized that DHA could react with hematin to form heme–dihydroartemisinin (H-DHA) and inhibit hematin crystallization. Thus, H-DHA is a potent antimalarial and the focus of this study.
In this work, we synthesized, detected, and purified the heme-dihydroartemisinin adduct (H-DHA) and evaluated its effects on hematin crystallization. We found that H-DHA acts as a weak kink blocker and does not inhibit the 2D nucleation of new crystal layers. Interestingly, its inhibitory effect was found to be irreversible. Using step velocity, rate of 2D nucleation, and step separation measurements, we quantified the effect of H-DHA on crystal growth. We observed that H-DHA moderately reduced the rate of hematin crystal growth.
To further investigate its impact on crystal formation, we employed dynamic light scattering, which revealed that H-DHA promotes crystal nucleation. Particle tracking analysis revealed that this enhanced nucleation is driven by an increase in nucleation precursor formation. Additionally, the irreversibility of H-DHA's effects suggests that elevated heme concentrations may promote β-hematin crystallization, resulting in the deposition of nanocrystals on the surface. These nanocrystalline deposits inhibit step propagation even in the absence of the drug. Our findings offer new insights into the mechanisms of action of ART-based drugs, highlighting the potential therapeutic role of H-DHA in malaria treatment.
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